Infertility is a major clinical problem in Western societies. A number of contributing factors have been identified for infertility, which include metabolic diseases in a male that result in insufficient sperm production and the inability of a female's ovaries to produce or release ova. In addition, pituitary disorders may cause infertility in both sexes because the gonads are responsive to regulation by pituitary hormones such as follicle-stimulating hormone and luteinizing hormone. However, clinical conditions exist in which an infertile female is still capable of ovulating. Therefore, the ovary may respond to additional signals that are not yet identified.
Zhang et al. (1994, Nature 372:425-432) describe the cloning and sequencing of the mouse ob gene and its human homolog. In an effort to understand the physiologic function of the ob gene, several independent research groups produced recombinant ob gene product in bacteria for in vivo testing (Pelleymounter et al., 1995, Science 269:540-543; Halaas et al., 1995, Science 269:543-546; Campfield et al., 1995, Science 269:546-549). When the Ob protein (also known as leptin) was injected into grossly obese mice, which possessed two mutant copies of the ob gene, the mice exhibited a reduced appetite and began to lose weight. Similarly, when normal mice received leptin, they also ate less than the untreated controls. Interestingly, when leptin was administered to ob/ob female mice which were always infertile, fertility was restored in these animals (Chehab et al., 1996, Nature Genetics 12:318-320).
Recently, a leptin fusion protein was generated and used to screen for the leptin receptor (also known as OB-R) in a cDNA expression library prepared from mouse choroid plexus, a tissue that lines brain cavities termed ventricles (Tartaglia, 1995, Cell 83:1263-1271). This approach led to the cloning of one form of the OB-R coding sequence, which reveals a single membrane-spanning receptor, sharing structural similarities with several Class I cytokine receptors, such as the gpl130 signal-transducing component of the interleukin-6 receptor (Taga et al., 1989, Cell 58:573-581), the granulocyte-colony stimulating factor receptor (Fukunaga et al., 1990, Cell 61:341-350), and the leukemia inhibitory factor receptor (Gearing et al., 1991, EMBO J. 10:2839-2848). Northern blot analysis and reverse transcription-polymerase chain reaction (RT-PCR) demonstrate that OB-R mRNA is expressed in several tissues, including lung, kidney, total brain, choroid plexus and hypothalamus.
The reported mouse OB-R protein contains a relatively short intracellular cytoplasmic domain as compared with other Class I cytokine receptors. Subsequently, when cDNA encoding its human homolog was isolated from a human infant brain library, the predicted human protein sequence contains a much longer intracellular domain. In view of this finding, it was speculated that different forms of the receptor might exist (Barinaga, 1996, Science 271:29). However, prior to the resent invention, there was no report on how variant forms of the OB-R in humans would relate to infertility.